Sarcoma
CME
Kyle D. Klingbeil, MD MS
General Surgery Resident
UCLA Health
LOS ANGELES, California, United States
Disclosure(s): No financial relationships to disclose
Kyle D. Klingbeil, MD MS
General Surgery Resident
UCLA Health
LOS ANGELES, California, United States
Disclosure(s): No financial relationships to disclose
Sarah M. Dry, MD
Department Chair, Pathology and Laboratory Medicine
UCLA Health, United States
Disclosure information not submitted.
Joseph G. Crompton, MD PhD
Assistant Professor, Division of Surgical Oncology
UCLA Health, United States
Disclosure information not submitted.
Fritz C. Eilber, MD
Professor of Surgery, Division of Surgical Oncology
UCLA Health, United States
Disclosure information not submitted.
David B. Shackelford, PhD
Associate Professor, Division of Pulmonary and Critical Care Medicine
UCLA Health, United States
Disclosure information not submitted.
Brian Kadera, MD (he/him/his)
Assistant Professor of Surgery
University of California, Los Angeles
Los Angeles, California, United States
Disclosure information not submitted.
Mitochondrial dynamics refers to the coordinated cycling of membrane fission and fusion events to modify structure and function. An imbalance in fission/fusion has been associated with disease progression for many cancers. Dynamin-Related Protein 1 (DRP1) plays a central role in mitochondrial fission and is activated through MAPK signaling by phosphorylation of serine residue 616 (pSer616). In this study, we explored mitochondrial dynamics within well-differentiated and dedifferentiated liposarcoma (WD/DD LPS), and targeted DRP1 as a novel therapeutic strategy.
Methods:
mRNA microarray analysis of WD/DD LPS patient tumor samples (n=47) was used to generate an expression heatmap for key regulators of mitochondrial dynamics. A Kaplan Meier curve associated DRP1 expression with overall survival. Western blots of cell lines 93T449 (WD LPS) and LPS2 (DD LPS) compared DRP1 and MAPK activation. Proliferation assays and western blots of LPS2 treated with DRP1 inhibitor (Mdivi-1) or MEK inhibitor (PD184352) were performed. Doxorubicin was given in combination to assess for chemo-sensitization. Fluorescent microscopy evaluated mitochondrial morphology under treatment conditions.
Results:
Among the key regulators of mitochondrial dynamics, DRP1 expression and activation (gain of pSer616 and loss of pSer637) was highly associated with dedifferentiation (Fig1A&C). DD LPS patients with DRP1+ tumors demonstrated a worse overall survival compared to DRP- tumors, log-rank p = 0.0181 (Fig1B). Treatment with Mdivi-1 or PD184352 led to a dose-dependent reduction in cell proliferation, and when combined with doxorubicin, improved chemosensitivity (Fig1D). PD184352 suppressed MAPK signaling and DRP1 activation (Fig1E). Fluorescent microscopy demonstrated LPS2 mitochondrial morphology shifts from a fragmented to elongated phenotype with either Mdivi-1 or PD184352 (Fig1F).
Conclusions:
DRP1 expression and activation are a hallmark of DD LPS. Pharmacologic inhibition of DRP1 by Mdivi-1 or PD184352 in vitro promotes an elongated mitochondrial morphology, reduces cell growth and enhances chemosensitivity. Further investigation into the dysregulation of mitochondrial dynamics may reveal a novel treatment strategy to overcome chemoresistance.